Terzis A J, Fiskerstrand T, Refsum H, Ueland P M, Arnold H, Bjerkvig R
Department of Neurosurgery, University of Lübeck, Germany.
Int J Cancer. 1993 Apr 22;54(1):112-8. doi: 10.1002/ijc.2910540118.
The present study describes the effects of 2 folate antagonists, methotrexate (MTX) and the lipophilic antifolate trimetrexate (TMX) on 2 permanent human glioma cell lines (GaMg and D-54Mg) grown as monolayers and as multicellular tumor spheroids. In addition, the effects of drug exposure on tumor cell invasion was studied using a three-dimensional organ co-culture system. In monolayer cultures, TMX was a more potent inhibitor of cell growth than MTX, especially towards the GaMg cell line. The 2 drugs, however, showed similar cytotoxicity as assessed by the plating efficiency assay. Reduced ability of directional migration of cells on a plastic surface was seen by either antifolate usually at concentrations to 10-fold higher than those exerting a cytotoxic effect in the plating efficiency assay. TMX was somewhat more potent than MTX as an inhibitor of spheroid growth. When tumor spheroids were exposed to MTX or TMX at concentrations that caused 65 to 70% inhibition of cell migration, there was a latent period of 4 to 5 days before inhibition of spheroid growth ensued. Invasion was investigated in a co-culture system, where tumor spheroids were confronted with fetal rat brain cell aggregates. Neither drug reduced tumor cell invasion, although histological examination revealed toxic effects both in GaMg and in D-54Mg spheroids. We conclude that spheroids from human glioma cells were less sensitive to the antifolates than monolayers. For both drugs a latency period was observed before inhibition of spheroid growth. The spheroids retained their ability to invade normal brain tissue when exposed to levels of folate antagonists inhibiting spheroid growth.
本研究描述了两种叶酸拮抗剂，甲氨蝶呤（MTX）和亲脂性抗叶酸药三甲曲沙（TMX）对两种人永久性胶质瘤细胞系（GaMg和D - 54Mg）的影响，这些细胞系以单层和多细胞肿瘤球体形式生长。此外，使用三维器官共培养系统研究了药物暴露对肿瘤细胞侵袭的影响。在单层培养中，TMX比MTX对细胞生长的抑制作用更强，尤其是对GaMg细胞系。然而，通过平板接种效率测定评估，这两种药物显示出相似的细胞毒性。通常在比平板接种效率测定中发挥细胞毒性作用高10倍的浓度下，两种抗叶酸药都能使细胞在塑料表面的定向迁移能力降低。作为球体生长的抑制剂，TMX比MTX稍强。当肿瘤球体暴露于导致细胞迁移抑制65%至70%的MTX或TMX浓度时，在球体生长受到抑制之前有4至5天的潜伏期。在共培养系统中研究了侵袭情况，在该系统中肿瘤球体与胎鼠脑细胞聚集体接触。尽管组织学检查显示在GaMg和D - 54Mg球体中都有毒性作用，但两种药物都没有降低肿瘤细胞的侵袭。我们得出结论，人胶质瘤细胞的球体对抗叶酸药的敏感性低于单层细胞。对于这两种药物，在球体生长受到抑制之前都观察到了潜伏期。当暴露于抑制球体生长的叶酸拮抗剂水平时，球体保留了侵入正常脑组织的能力。
